FORM 2
THE PATENTS ACT. 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(Sec section 10)
"A PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE
I- (AMINOMETHYL)-1-CYCLOHEXANEACETICAClD"
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated .under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD ANDHERI (E), MUMBAI-400059. MAHARASHTRA, INDIA

.


The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

"A PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE
I-(AMININOMETHYL)-I-CYCLOHEXANEACETIC ACID"
The present invention relates to a process for the preparation of substantially pure 1-(aminomethyl)-l-cyclohexaneacetic acid, a compound of formula I commonly known as gabapentin. Gabapentin is a water-soluble chemical entity which is therapeutically useful in treatment of cerebral disease such as epilepsy.

Particularly the method relates to preparation of substantially pure 2-azaspiro[4,5]decan-3 one, hereinafter referred to as gabapentin lactam, a compound of formula II, which is then converted to gabapentin easily.

Formula II
BACKGROUND OF THE INVENTION
United States Patent No. 4,024,175 (Indian reference not available) describes different methods of preparing cyclic amino acids like gabapentin from cyclohcxyl-1,1-diacetic acid derivatives. The patent teaches preparation of gabapentin from Hoffmann rearrangement of i, 1-cyclohexane-diacetic acid monoamide, a compound of formula III by reacting with NaOBr. The reaction mixture
2

Formula III
is heated at 60° C for 2 hr. The work-up includes acidification and extraction with methylene chloride and evaporation of aqueous phase to obtain gabapentin hydrochloride, which is converted to gabapentin by treatment with an anion exchange resin and further crystallised from ethanol/ether. We found the use of basic ion-exchange resin for the isolation of gabapentin to be very tedious and time consuming. The method also required very careful monitoring of fractions eluting out of the resin columns, otherwise the product got invariably contaminated with chloride ions and failed to meet our quality specifications. Yet another problem associated with the use of resins, on large-scale operations, is that the eluale contains gabapentin at a concentration of the order of only about 1.5 to 2%, whose distillation required high-energy consumption and engagement of other infrastructure like-vacuum and long occupancy of reaction vessels due to slow evaporation of water.
United States Patent No. 5,068,413 (Indian reference not available) discloses hydrolysis of ,., diethyl 1 -cyanocyclohexyl malonate to (1 -cyanocyc!ohexyl)-malonic acid followed by decarboxylation and hyd'rogenation to yield gabapentin. This involves high pressure * " hydrogenation in the presence of expensive catalyst like Raney nickel, Raney cobalt or noble metal catalysts, for example rhodium or palladium, optionally in a carrier such as carbon.
United States Patent No. 5,091,567 (Indian reference not available) discloses preparation of gabapentin via 5 steps viz. (a) reacting cyciohexanone with triethyl phosphonoacetic acid and a base to produce ethyl cyclohexylideneacetate (b) reaction of ethyl cyclohexylideneacetate with nitromethane to produce ethyl 1-nitromethyl-l-cyclohexaneacetate (c) reducing the nitro compound with hydrogen in the presence of a noble catalyst to give a mixture of ethyl 1 -aminomethyl-1-cyclohexaneacetate and 2-aza-spiro[4,5]-decan-3-one. (d) conversion of the mixture obtained in step (c) to gabapentin salt using a dilute acid followed by (e) converting the salt to gabapentin using a weakly basic anion exchanger. This process is cumbersome and
3

involves use of an uncommon chemical triehyl phosphonoacetic acid, high pressure hydrogenation in the presence of noble catalyst and weakly basic anion exchanger.
United States Patent No. 5,362,883 (Indian reference not available) process describes preparation of gabapentin lactam by reaction of I :cyanocyclohexaneacetonitrile with ethanol in the presence of an acid followed by hydrolysis and hydrogenation. This process also involves high pressure hydrogenation.
European Patent No. 414263 (Indian reference not available) describes conversion of gabapentin lactam to gabapentin by acidic hydrolysis followed by ion exchange chromatography which is tedious and time consuming.
The applicants prepared gabapentin according to the process disclosed in United States
Patent No. 4,024,175 wherein 1,1-cyclohcxancdiacclic acid monoamide was subjected to Hofmann rearrangement by reacting with bromine and alkali to form gabapentin. However, the yield was not satisfactory. Wc investigated the reasons for low yield of gabapentin. A series of experiments were monitored by 13C NMR and the study revealed that during the Hofmann reaction a sizeable amount of gabapentin lactam was being formed along with
some other side products. In order to isolate pure gabapentin from the" reaction mixture it was necessary to remove (i) unwanted side products (ii) large quantities of inorganic byproducts like sodium bromide, sodium chloride and (iii) high volumes of water. The formation of significant amount of lactam and the additional steps required for isolation cf pure gabapentin made the process commercially inefficient. Hence it wais necessary to develop a simpler methodology for the isolation of gabapentin from the Hoffmann reaction mixture.
The applicants questioned that instead of isolation of gabapentin in a pure form by the laborious work-up procedure, whether they could isolate a gabapentin precursor in a pure
form and in high yield by a simple extraction procedure, and then obtain the gabapentin in substantially pure form from the precursor by a simple method. For this purpose the
applicants identified gabapentin lactam as the precursor for preparation of gabapentin
because significant amount of lactam is formed during the course of the reaction.
4

Thus, the objective of the present invention was to develop a convenient method suitable for isolation of gabapentin precursor, the gabapenlin lactam in pure form, which could in turn be converted to gabapenlin easily. The lactam can be converted to gabapentin hydrochloride, whereupon gabapentin may be isolated directly from the aqueous solution. A novel method
of isolating gabapentin directly from the aqueous solution without the use of ion exchange resins is the subject of a separate Indian Patent Application being filed simultaneously with this application.
The isolation of lactam was studied by following the reaction conditions described in United States Patent No. 4,024,175 upto the Hofmann rearrangement step, further the reaction mixture was acidified and heated to obtain the lactam. However, the lactam obtained was not pure thus inferring that, possibly during the course of the reaction some intermediate(s) underwent side reactions resulting in the formation of unwanted products (Organic
Reactions, Vol-Ill, pg 267, 1946).
To optimise the conditions for quantitative lactam formation, we investigated the lactam formation process taking pure gabapentin as the starting material and subjecting it to acidic conditions in order to identify any possible side reactions. However it resulted in clean
lactam formation with about 60 % yield and the balance amount of starting material Was recovered unchanged. The recovery of starting material suggested that either the reaction
time was not sufficient or pH is not suitable for the facile formation of lactam. The reaction was studied at different pH values and the result is summarised in Table I.
Table I

Exp it Mole Ratio pH Temp. (°G) Time (hr) Yield (%)
Gabapentin HCI
1 1 0.81 3.0 Reflux 4 59
2 1 0.24 4.0 Reflux 4 60
3 1 0.04 5.5 Reflux 4 6.4
4 1 0.00 6.8 Reflux 4 9.5
5

Since the best results were observed at pH 3 to 4. changes in time and temperature
parameters were extensively studied to optimise the conversion of gabapentin u» lactam. However, the yields obtained were not satisfactory to adopt the process.
The applicants further studied the pH ranges towards alkaline side which we initially had inhibition to study as the carboxylates are not good substrates for the lactam formation reactions. To their surprise the applicants found that when the reaction was performed at pH
85 the reaction took place in a facile manner, and the pH of the mother liquor was around 14. Based on this observation the applicants studied the reaction at pH 14. Although under highly basic conditions (Table II) the gabapentin exists exclusively as the carboxylate front which the applicants expected lactam formation to be difficult, the applicants surprisingly found that lactam formation was facile under these conditions.
Table II

Exp # Mole Ratio Gabapentin/Base Pll Temp. (°C) Time (hr) Yield (%)
1 1:1.07(NaOH) 14.0 Reflux 4
2 , 1:0.50(NaHCO3)—i 8.5 Reflux ~* 4 <)
It was surprisingly found that the reaction mixtures containing gabapentin could be converted quantitatively to lactam and isolation of substantially pure lactam could be carried out by simple extraction. Hydrolysing the substantially pure 2-azaspiro(4,5]decan-3-one to gabapentin salt with an acid; neutralisation with a base to precipitate* gabapentin and isolation of precipitated gabapentin provided a facile method for preparation of substantially pure gabapentin.
The process disclosed and claimed relates to the preparation of substantially pure gahapentin comprising :
(a) treating crude gabapentin with an alkali such that the pH of the reaction mixture is at least 7.5; heating the reaction mixture to a temperature of at least about 80o C and
6

maintaining said temperature for ;ii least about 30 minutes; extraction into an organic solvent such as herein described followed by isolation of substantially pure 2-azaspiro[4.5]decan-3-one, a compound of formula II, from the organic solvent by conventional means;
(b) hydrolysing the substantially pure 2-azaspiro[4,5]decan-3-one with an acid to obtain gabapentin salt; neutralisation of the salt with a base to precipitate gabapentin and isolation of precipitated gabapentin.
SUMMARY OF THE INVENTION:
The present invention relates to a process for the preparation of substantially pure 1-(aminomethyl)-l-cyclohexaneacetic acid, a compound of formula I i.e. gabapentin

comprising
(a) treating crude gabapentin with an alkali such that the pH of the reaction mixture is at least 7,5; heating the reaction mixture to a temperature of at least about 80°C and maintaining said temperature for at least about 30 minutes; extraction into an organic solvent such as heroin described followed' by isolation of substantially pure 2-azaspiro[4,5)decan-3-one, a compound of formula If, from the organic solvent by conventional means; J "
(b) hydrolysing the substantially pure 2-azaspiro[4,5]decan-3-one with an acid to obtain gabapentin salt; neutralisation of the salt with a base to precipitate gabapentin and isolation of precipitated gabapentin.
The crude gabapentin may be generated in-situ, preferably by Hofmann rearrangement reaction between 1,1-cyclohexane diacetic acid monoamide (III) with a hypo halite. The hypo halite may also be generated in-situ by reaction of a halogen with an alkali.

DETAILED DESCRIPTION AND SCOPE OF THE PRESENT INVENTION
According to a preferred aspect of the present invention the process comprises treating crude gabapentin with an alkali such that the pH of the reaction mixture is at least 9; heating the reaction mixture to a temperature of about 95°C to about 100°C and maintaining said temperature for at least about 2 hr: extraction into an organic solvent followed by isolation of substantially pure 2-azaspiro[4,5]decan-3-one, a compound of formula II. from the organic solvent by conventional means; hydrolysing the substantially pure 2-azaspiro[4,5]decan-3-one with an acid to obtain gabapentin salt; neutralisation of the salt with a base to precipitate gabapentin and isolation of precipitated gabapentin.
In a preferred embodiment of the present invention the crude gabapentin is reacted with an alkali by raising the reaction temperature to 90 to 105° C and maintaining said temperature for 30 minutes or more, preferably for 2 hr or more, and more preferably for 3 hr or more.
In more preferred embodiments of the present invention the crude gabapentin is reacted with
an alkali by raising the reaction temperature to 95 to !00° C and maintaining said
temperature for 30. minutes or more, preferably for 2 hr or more, and more preferably for 3 hr
or more. .
(A) Starting Materials : Crude Gabapentin
As referred to herein, the substantially pure gabapentin prepared according to the process of

The present invention is gabapentin in which the sum of all impurities as determined by
HPLC is not more than 1% and assay (on dried basis ) is 98.00 to 102.00% Crude gabapentin which is not substantially pure. Crude gabapentin cording to the process of the present invention also refers to gabapentin obtained in-situ by hitherto known processes such as described herein.
As referred to herein, substantially pure gabapentin lactam is gabapentin lactam as determined by HPLC to be more than 99% pure.
8

(B) Preparation of substantially pure gabapentin lactam
According to the process of the present invention the preparation of substantially pure gabapentin lactam

comprises treating crude gabapentin with an alkali such that the pH of the reaction mixture is at least 7.5; heating the reaction mixture to a temperature of at least about 80°C and maintaining said temperature for at least about 30 minutes; extraction into an organic solvent followed by isolation of substantially pure 2-azaspiro[4,5]decan-3-onc i.e. gabapentin lactam, a compound of formula II, from the organic solvent by conventional means.

Formula II
The solvent used in the steps of exraction and isolation is selected from Dichloromethane. Dichloroethane, Toluene Eylacetate, n-butanol, Diisopropyl either and Methyl
isobutyiketone. The preferred solvents are Dichloromethane, Dichloroethane and Toluene,
and, most preferred being Dichloromethane.
In .a preferred embodiment of the present invention the crudegabapentin is reacted with an alkali by raising the reaction temperature to 90 to 105° C and maintaining said temperature for 30 minutes or more, preferably for 2 hr or more, and more preferably for 3 hr or more.
In more preferred embodiments of the present invention the crude gabapentin is reacted with an alkali by raising the reaction temperature to 95 to 100° C and maintaining said
9

temperature for 30 minutes or more, preferably for 2 hr or more, and more preferably for 3 hr or more.
In a particularly preferred embodiment of the process of the present invention the crude gabapentin may be generated in-situ, by a process comprising reacting 1,1-cyclohexane diacetic acid monoamide (III) with a hypohalitc.
In still more preferred embodiments of the present invention the hypo halite may be generated in-situ by reaction of an alkali and a halogen.
The molar ratios of halogen to alkali to monoamide that may be used are such that reaction mixture is alkaline. The pH may be greater than 7.5, preferably greater than 9 and more preferably greater than 12. The molar ratios of halogen to alkali to monoamide may be I to 1.5 of halogen to 2 to 9 of alkali to 1 of monoamide. Preferably the molar ratios are 1.1 to 1.5 of halogen to 7 to 9 of alkali to 1 of monoamide. More preferably the molar ratios arc 1.1 to 1.2 of halogen to 5.5 to 6.5 of alkali to 1 of monoamide.
The halogen maybe chlorine or bromine, preferably bromine and (Its' alkali is an alkaiimetal
, or alkaline-earth metal hydroxide, carbonate, bicarbonate, oxide ot mixtures thereof.
, Examples of alkali metal hydroxides that may be used include NaOK, KOH, LiOH, and
CsOH. More preferably the hydroxide is sodium hydroxide. According to the most preferred
embodiment the halogen is bromine and the alkali is sodium hydroxide.
Isolation of Gabapentin Lactam
According, to the process of the present invention the gabapentin lactam may be isolated in a substantially pure form from the reaction mixture. The gabapentin lactam is extracted into an organic solvent. A. preferred organic solvent is dichloromethane. The gabapentin lactam may be isolated in a substantially pure form from the organic solvent by conventional means such as removal of organic solvent by evaporation, crystallisation or precipitation by known methods such as temperature change, non-solvent addition and the like.
10

(C) Preparation of substantially pure gahapentin
The lactam obtained from the process of the present invention may be converted to gabapentin hydrochloride by aqueous acidic hydrolysis. The gabapentin hydrochloride is then suspended in minimum amount of water and neutralised to appropriate pH with NaOH to crystallise gabapentin directly from water. The mother liquor obtained in any of the steps of the process may be recycled i.e. added in the appropriate prior step of the process such as lactam formation or lactam hydrolysis or gabapentin neutralisation in order to improve the overall efficiency of the process.
The preferred solvent for aqueous acidic hydrolysis are water, aqueous PEG-400 to 10,000 (0%-60% vol/vol) and aqueous alcohol (0%-10% vol/vol), the most preferred being water.
In acidic hydrolysis the solvent ration of PEG (400 to 800)water can range from 1:100 to 60:100 parts by volume and alcohohlwateration can range from 1:100 to 10:100 parts by volume.
The present invention is illustrated by but not limited to the description in the following examples

EXAMPLE I Preparation of substantially pure gabapentin lactam:
To a solution of 20 g crude gabapentin in 100 ml water at room temperature was added a solution of 5 g NaOH in 15 ml water. The pH of the reaction mixture was 14. The reaction temperature was raised to 98 to 100° C so as to reflux the reaction mixture and the reflux temperature maintained for a period of 4 hr. The reaction mixture was cooled to 30 to 35°C and the lactam was extracted into 100 ml dichloromcthane. Dichloromethane was evaporated under vacuum at 35 to 40° C completely and the solid lactam further subjected to the vacuum for 2 hr to.removc the traces of solvent. The yield of lactam was 17.4 g (97 %). The purity as determined by HPLC was > 99%.
EXAMPLE 2
Preparation of substantially pure gabapentin lactam
The procedure of example 1 was followed except that 2.7 g Na HCO3 was used instead of sodium hydroxide so that the pH of the reaction mixture was 8.5. The yield of of lactam was g (96.4 %). The purity as determined by HPLC was > 99%.


To a 300 ml of 20 %,(w/y) aqueous sodium hydroxide solution, was added under-siring
14.7 ml (0.276 mole) bromine, the reaction temperature was maintained between 0 to 5°C,
ever c period of about 1 hr. The resultant yellow coloured solution was further maintained at
0 'to 2°C for 30 minutes. To the above solution was gradually added, 50 g (0.250 mole) of
11-cyclolohexanediacetic acid monoamide maintaining the .reaction mixture temperature
between 0 to 5°C. The reaction mixture was maintained under stirring at 0 to 5°C for 2 hr. The external coolant was removed and the temperature of the reaction mixture allowed to rise , to. 25 to 35°C on its own. Gab pent referred to herein as crude gabapentin is formed in the reaction mixture. The reaction temperature was slowly raised to 73 to 75°C over a period of 30 to 40 minutes and maintained for a period of 2 hr. The reaction temperature was raised to 98 to 100°C so as to reflux the reaction mixture and maintained at reflux temperature for a period of 4 hr. The reaction mixture was cooled to 30 to 35°C and the lactam extracted into 150 ml of dichloromethane. The product-enriched dichloromethane was concentrated under
12

vacuum at 35 to 40°C, completely and the solid lactam further degassed under the same conditions for 2 hr to remove the traces of solvent. The yield of lactam was 30 g (97%). The purity as determined by HPLC was > 99%.
EXAMPLE 4 Preparation of substantially pure gabapentin :
Lactam obtained by any of examples 1 to 3 is treated as illustrated herein. Lactam (454 g), obtained by the process as given in any of the examples 1 to 3, was suspended in a mixture of water (1135 ml) and hydrochloric acid (1135 ml) and refluxed for about 6 hr (105°C-107°C). Water was distilled out and the slurry obtained was gradually cooled to room temperature. Acetone (-1000 ml) was added and stirred at 0°C-5 °C for 30 min. The reaction mixture was filtered and the crude gabapentin hydrochloride was washed with acetone (100 ml). The steps of addition of acetone, cooling and filtration were repeated with the mother liquor twice. The total gabapentin hydrochloride isolated was 541 g.
Gabapentin hydrochloride (530 g) was then dissolved by heating in demincralised watch." (265 ml) at 50°C - 55°C and cooled to room temperature: Sodium hydroxide lye (145 g) was slowly added to it until the aqueous mixture reached a pH between 7.4 i& 7.8 (about 6 hr), at . temperature between !5°C to 20 °C and further stirred a-;his temperature for 30 miu. The reaction mixture was cooled. 0°C-5°C and maintained for about 7 hr. The crystallized product was filtered, washed with water (90-95 ml), followed by washing with chilled methanol, (185 ml) to obtain gabapentin (315 g). h was washed with acetone (1:10 mole ratio] gabapentm:acetone) by stirring at 25 °C -30 °C for about 1 hr. The product was filtered and Washed with acetone, and then dried in air oven at 65 °G -70 °G .for 30 min. -
13

We claim
1. A process for the preparation of substantially pure l-(aminomethyl)-l-cyclohexaneacetic acid, a compound of formula I i.e. gabapentin

Formula I
comprising
(a) treating the crude gabapentin with an alkali such that the pH of the reaction mixture is at least 7.5; heating the reaction mixture to a temperature of at least about 80°C and maintaining said temperature for at least about 30 minutes; extraction into an organic solvent such as herein described followed by isolation of substantially pure 2-azaspiro[4,5]decan-3-one, a compound of formula II)

2. A process as claimed in claim 1 wherein the pH of the reaction mixture is at least 9.
14

3. A process as claimed in claim 1 wherein the reaction mixture is heated to a temperature of between 95°C to 100°C and said temperature is maintained for at least about 2 hours.
4. A processes claimed in claims ,1 ,to, 3 substantially as herein described and illustrated by examples 1 to 4.
Dated this 10th day of January 2000

15